Alcohol is a trait with moderate heritability for which only a small number of risk loci have been identified. Linkage studies have located several genomic regions that are likely to contain susceptibility loci. The goal of this project is to refine and extend findings from previous genome-wide scans for loci causing predisposition for alcohol using linkage disequilibrium (LD) based techniques, such as the transmission- disequilibrium test (TDT; Spielman et al., 1993) in order to identify specific genes influencing risk. We will study LD between DNA regions identified by previous alcohol dependence genomes and studies (COGA study, Reich et al. 1998; NIAAA study, Long et al. 1998) as being lined to alcohol dependence and, in particular, P300 amplitude reductions in the COGA group (Williams et al, 1999) in three samples of small nuclear families (SNFs), principally family trios. We project that the total projected sample of 400 trios (proband plus DNA from both parents) will include a subgroup of at least 100 trios collected in the context of this Center where probands have completed P300 assessment; and 150 already-collected families. In addition we will have access to at least 150 cocaine-dependent subjects have co-morbid alcohol dependence, yielding a total sample of 400 SNFs. This project is designed under the assumption that semi-automated short tandem repeat (STR) genotyping will be employed, but with the flexibility to substitute chip array genotyping, should this be feasible by YR03 when large-scale genotyping is planned to begin. We will screen for new polymorphisms to help attempts to narrow the genomic region interest, and also, potentially to identify actual functional variants underlying a portion of the phenotyping variability of this disorder.